Heavy Menstrual Bleeding, Uterine Fibroids
Conditions
Keywords
Elagolix, Elagolix Sodium, Heavy uterine bleeding, Heavy menstrual bleeding (HMB), Leiomyomata, Menorrhagia, ABT-620, Elagolix + E2/NETA (Elagolix + Norethindrone acetate)
Brief summary
This study seeks to evaluate the efficacy, safety and tolerability of elagolix alone and in combination with estradiol/norethindrone acetate for the management of heavy menstrual bleeding associated with uterine fibroids in premenopausal women.
Interventions
DRUGElagolix
Film-coated tablets
Placebo capsules
Commercially-available E2/NETA tablets were over-encapsulated to maintain study blinding.
Film-coated placebo tablets
Sponsors
AbbVie
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 51 Years
Healthy volunteers
No
Inclusion criteria
* Subject is a premenopausal female at the time of Screening. * Subject has a diagnosis of uterine fibroids documented by a pelvic ultrasound (transabdominal ultrasound/transvaginal ultrasound). * Subject has heavy menstrual bleeding associated with uterine fibroids as evidenced by menstrual blood loss \> 80 mL during each of two screening menses as measured by the alkaline hematin method. * Subject has negative urine and/or serum pregnancy test in Screening and just prior to first dose. * Subject has an adequate endometrial biopsy performed during Screening, the results of which show no clinically significant endometrial pathology.
Exclusion criteria
* Subject has screening pelvic ultrasound or saline infusion sonohysterography results that show a clinically significant gynecological disorder. * Subject has history of osteoporosis or other metabolic bone disease. * Subject has clinically significant abnormalities in clinical chemistry, hematology, or urinalysis. * Subject has a history of major depression or post-traumatic stress disorder (PTSD) within 2 years of screening, OR a history of other major psychiatric disorder at any time (e.g., schizophrenia, bipolar disorder). * Subject is using any systemic corticosteroids for over 14 days within 3 months prior to Screening or is likely to require treatment with systemic corticosteroids during the course of the study. Over the counter and prescription topical, inhaled, intranasal or injectable (for occasional use) corticosteroids are allowed.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Meeting the Criteria for Responder | Final Month (the last 28 days prior to and including the Reference Day), up to Month 6 | Percentage of responders, defined as participants who met the following conditions: * Menstrual blood loss (MBL) volume \< 80 mL during the Final Month (the last 28 days prior to and including the Reference Day, which is defined as the last visit date during the Treatment Period (last treatment visit date) or the last dose date if there are evaluable alkaline hematin data after the last treatment visit date and prior to or on the last dose date), and * ≥ 50% reduction in MBL volume from Baseline to the Final Month. Participants who prematurely discontinued study drug due to lack of efficacy, requires surgery or invasive intervention for treatment of uterine fibroids, or adverse events were considered non-responders regardless of whether she meets the two aforementioned responder criteria or not. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Suppression of Bleeding at the Final Month | Final Month (the last 28 days prior to and including the Reference Day), up to Month 6 | Suppression of bleeding is defined as having 0 days of bleeding (spotting is allowed) during the Final Month with the interval starting from Study Day 11. The Reference Day is defined as the last visit date during the Treatment Period (last treatment visit date) or the last dose date if there are evaluable alkaline hematin data after the last treatment visit date and prior to or on the last dose date. |
| Change From Baseline in MBL Volume to Month 6 | Month 0 (Baseline), Month 6 | Baseline MBL volume was defined as the mean of total MBL volume from all the qualified menstrual cycles during the Screening Period, in which the total MBL volume is from all validated and non-validated sanitary products and the MBL volume of validated sanitary products only (excluding non-validated sanitary products) was greater than 80 mL. |
| Change From Baseline in MBL Volume to the Final Month | Baseline and Final Month (the last 28 days prior to and including the Reference Day), up to Month 6 | Baseline MBL volume was defined as the mean of total MBL volume from all the qualified menstrual cycles during the Screening Period, in which the total MBL volume is from all validated and non-validated sanitary products and the MBL volume of validated sanitary products only (excluding non-validated sanitary products) was greater than 80 mL. The Reference Day is defined as the last visit date during the Treatment Period (last treatment visit date) or the last dose date if there are evaluable alkaline hematin data after the last treatment visit date and prior to or on the last dose date. |
| Percentage of Participants With Baseline Hemoglobin <= 10.5 g/dL Who Have an Increase in Hemoglobin > 2 g/dL at Month 6 | Month 0 (Baseline), Month 6 | — |
| Change From Baseline in MBL Volume to Month 1 | Month 0 (Baseline), Month 1 | Baseline MBL volume was defined as the mean of total MBL volume from all the qualified menstrual cycles during the Screening Period, in which the total MBL volume is from all validated and non-validated sanitary products and the MBL volume of validated sanitary products only (excluding non-validated sanitary products) was greater than 80 mL. |
| Change From Baseline in MBL Volume to Month 3 | Month 0 (Baseline), Month 3 | Baseline MBL volume was defined as the mean of total MBL volume from all the qualified menstrual cycles during the Screening Period, in which the total MBL volume is from all validated and non-validated sanitary products and the MBL volume of validated sanitary products only (excluding non-validated sanitary products) was greater than 80 mL. |
Countries
Canada, United States
Participant flow
Pre-assignment details
Eligible participants were randomized in a 1:1:2 ratio to 1 of 3 treatment groups: placebo, elagolix 300 mg BID, or elagolix 300 mg twice daily (BID) plus estradiol/norethindrone acetate (E2/NETA) once daily (QD).
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo for both elagolix BID and E2/NETA QD | 94 |
| Elagolix Elagolix 300 mg BID and placebo for E2/NETA (estradiol 1.0 mg/norethindrone acetate 0.5 mg) QD | 95 |
| Elagolix + E2/NETA Elagolix 300 mg BID and E2/NETA (estradiol 1.0 mg/norethindrone acetate 0.5 mg) QD | 189 |
| Total | 378 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Post-Treatment Follow-Up Period | Lost to Follow-up | 2 | 3 | 4 |
| Post-Treatment Follow-Up Period | Non-Compliance | 0 | 1 | 1 |
| Post-Treatment Follow-Up Period | Other | 2 | 1 | 1 |
| Post-Treatment Follow-Up Period | Required Surgery/Invasive Intervention | 0 | 0 | 3 |
| Post-Treatment Follow-Up Period | Withdrawal by Subject | 1 | 2 | 8 |
Baseline characteristics
| Characteristic | Placebo | Elagolix | Elagolix + E2/NETA | Total |
|---|---|---|---|---|
| Age, Continuous | 42.5 years STANDARD_DEVIATION 5.43 | 42.2 years STANDARD_DEVIATION 5.41 | 42.5 years STANDARD_DEVIATION 5.33 | 42.4 years STANDARD_DEVIATION 5.36 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 11 Participants | 17 Participants | 31 Participants | 59 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 83 Participants | 78 Participants | 158 Participants | 319 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 2 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 63 Participants | 66 Participants | 124 Participants | 253 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 3 Participants | 3 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 30 Participants | 27 Participants | 59 Participants | 116 Participants |
| Sex: Female, Male Female | 94 Participants | 95 Participants | 189 Participants | 378 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 94 | 0 / 95 | 0 / 189 |
| other Total, other adverse events | 34 / 94 | 58 / 95 | 80 / 189 |
| serious Total, serious adverse events | 1 / 94 | 4 / 95 | 7 / 189 |
Outcome results
Primary
Percentage of Participants Meeting the Criteria for Responder
Percentage of responders, defined as participants who met the following conditions: * Menstrual blood loss (MBL) volume \< 80 mL during the Final Month (the last 28 days prior to and including the Reference Day, which is defined as the last visit date during the Treatment Period (last treatment visit date) or the last dose date if there are evaluable alkaline hematin data after the last treatment visit date and prior to or on the last dose date), and * ≥ 50% reduction in MBL volume from Baseline to the Final Month. Participants who prematurely discontinued study drug due to lack of efficacy, requires surgery or invasive intervention for treatment of uterine fibroids, or adverse events were considered non-responders regardless of whether she meets the two aforementioned responder criteria or not.
Time frame: Final Month (the last 28 days prior to and including the Reference Day), up to Month 6
Population: All randomized and treated participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants Meeting the Criteria for Responder | 10.5 percentage of participants |
| Elagolix | Percentage of Participants Meeting the Criteria for Responder | 76.9 percentage of participants |
| Elagolix + E2/NETA | Percentage of Participants Meeting the Criteria for Responder | 76.5 percentage of participants |
p-value: <0.00195% CI: [12.248, 67.387]Regression, Logistic
p-value: <0.00195% CI: [13.042, 61.431]Regression, Logistic
Secondary
Change From Baseline in MBL Volume to Month 1
Baseline MBL volume was defined as the mean of total MBL volume from all the qualified menstrual cycles during the Screening Period, in which the total MBL volume is from all validated and non-validated sanitary products and the MBL volume of validated sanitary products only (excluding non-validated sanitary products) was greater than 80 mL.
Time frame: Month 0 (Baseline), Month 1
Population: All randomized and treated participants with an assessment at given time point.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in MBL Volume to Month 1 | -2.1 mL | Standard Error 14.31 |
| Elagolix | Change From Baseline in MBL Volume to Month 1 | -196.6 mL | Standard Error 14.74 |
| Elagolix + E2/NETA | Change From Baseline in MBL Volume to Month 1 | -127.0 mL | Standard Error 10.14 |
p-value: <0.001mixed model repeated measures
p-value: <0.001mixed model repeated measures
Secondary
Change From Baseline in MBL Volume to Month 3
Baseline MBL volume was defined as the mean of total MBL volume from all the qualified menstrual cycles during the Screening Period, in which the total MBL volume is from all validated and non-validated sanitary products and the MBL volume of validated sanitary products only (excluding non-validated sanitary products) was greater than 80 mL.
Time frame: Month 0 (Baseline), Month 3
Population: All randomized and treated participants with an assessment at given time point.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in MBL Volume to Month 3 | -14.2 mL | Standard Error 11.57 |
| Elagolix | Change From Baseline in MBL Volume to Month 3 | -211.1 mL | Standard Error 11.96 |
| Elagolix + E2/NETA | Change From Baseline in MBL Volume to Month 3 | -200.3 mL | Standard Error 8.17 |
p-value: <0.001mixed model repeated measures
p-value: <0.001mixed model repeated measures
Secondary
Change From Baseline in MBL Volume to Month 6
Baseline MBL volume was defined as the mean of total MBL volume from all the qualified menstrual cycles during the Screening Period, in which the total MBL volume is from all validated and non-validated sanitary products and the MBL volume of validated sanitary products only (excluding non-validated sanitary products) was greater than 80 mL.
Time frame: Month 0 (Baseline), Month 6
Population: All randomized and treated participants with an assessment at given time point.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in MBL Volume to Month 6 | 28.5 mL | Standard Error 16.68 |
| Elagolix | Change From Baseline in MBL Volume to Month 6 | -223.7 mL | Standard Error 17.98 |
| Elagolix + E2/NETA | Change From Baseline in MBL Volume to Month 6 | -198.1 mL | Standard Error 11.89 |
p-value: <0.001mixed model repeated measures
p-value: <0.001mixed model repeated measures
Secondary
Change From Baseline in MBL Volume to the Final Month
Baseline MBL volume was defined as the mean of total MBL volume from all the qualified menstrual cycles during the Screening Period, in which the total MBL volume is from all validated and non-validated sanitary products and the MBL volume of validated sanitary products only (excluding non-validated sanitary products) was greater than 80 mL. The Reference Day is defined as the last visit date during the Treatment Period (last treatment visit date) or the last dose date if there are evaluable alkaline hematin data after the last treatment visit date and prior to or on the last dose date.
Time frame: Baseline and Final Month (the last 28 days prior to and including the Reference Day), up to Month 6
Population: All randomized and treated participants.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in MBL Volume to the Final Month | -4.3 mL | Standard Error 15.44 |
| Elagolix | Change From Baseline in MBL Volume to the Final Month | -198.8 mL | Standard Error 15.44 |
| Elagolix + E2/NETA | Change From Baseline in MBL Volume to the Final Month | -168.8 mL | Standard Error 10.72 |
p-value: <0.001ANCOVA
p-value: <0.001ANCOVA
Secondary
Percentage of Participants With Baseline Hemoglobin <= 10.5 g/dL Who Have an Increase in Hemoglobin > 2 g/dL at Month 6
Time frame: Month 0 (Baseline), Month 6
Population: All randomized and treated participants with baseline hemoglobin \<= 10.5 g/dL and an assessment at Month 6.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With Baseline Hemoglobin <= 10.5 g/dL Who Have an Increase in Hemoglobin > 2 g/dL at Month 6 | 20.8 percentage of participants |
| Elagolix | Percentage of Participants With Baseline Hemoglobin <= 10.5 g/dL Who Have an Increase in Hemoglobin > 2 g/dL at Month 6 | 40.0 percentage of participants |
| Elagolix + E2/NETA | Percentage of Participants With Baseline Hemoglobin <= 10.5 g/dL Who Have an Increase in Hemoglobin > 2 g/dL at Month 6 | 50.0 percentage of participants |
p-value: 0.14695% CI: [-5.99, 44.32]chi-square or Fisher's exact test
p-value: 0.01795% CI: [7.62, 50.71]chi-square or Fisher's exact test
Secondary
Percentage of Participants With Suppression of Bleeding at the Final Month
Suppression of bleeding is defined as having 0 days of bleeding (spotting is allowed) during the Final Month with the interval starting from Study Day 11. The Reference Day is defined as the last visit date during the Treatment Period (last treatment visit date) or the last dose date if there are evaluable alkaline hematin data after the last treatment visit date and prior to or on the last dose date.
Time frame: Final Month (the last 28 days prior to and including the Reference Day), up to Month 6
Population: All randomized and treated participants with an assessment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With Suppression of Bleeding at the Final Month | 4.7 percentage of participants |
| Elagolix | Percentage of Participants With Suppression of Bleeding at the Final Month | 88.9 percentage of participants |
| Elagolix + E2/NETA | Percentage of Participants With Suppression of Bleeding at the Final Month | 61.0 percentage of participants |
p-value: <0.00195% CI: [75.99, 92.37]chi-square or Fisher's exact test
p-value: <0.00195% CI: [47.77, 64.91]chi-square or Fisher's exact test